Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

18F-fluciclovine PET/CT to distinguish radiation necrosis from tumor progression for brain metastases treated with radiosurgery: results of a prospective pilot study.

PURPOSE: Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We performed a prospective pilot study to determine whether PET/CT with 18F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions. METHODS: Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an 18F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation. RESULTS: Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUVmax statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUVmean (AUC = 0.875; p = 0.018), SUVpeak (AUC = 0.813; p = 0.007), and SUVpeak-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUVmax-to-normal-brain (p = 0.1) and SUVmean-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2). CONCLUSIONS: In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression, 18F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance.

Standardizing Methods of Reading CT Maximum Aortic Diameters Amongst Experts Reduces Variations and Discordance, Improving Accuracy.

BACKGROUND: There is no consensus on the method of obtaining abdominal aortic aneurysm (AAA) maximum diameters based on computed tomographic angiography, and the reproducibility and accuracy of different methods have recently been debated due to advancements in imaging. This study compared the two most common methods based on orthogonal planes and centerline of flow to determine the discordances and accuracy amongst experiences readers. METHODS: The computed tomographic angiography max diameters of 148 AAAs were measured by three experienced observers, including a vascular surgeon, a radiologist and an imaging cardiologist. Observers used two different methods with standardized protocols: multiplanar reformations based on orthogonal planes, and a software using 3D aortic reconstructions to create centerline flow lumen providing diameters based on cross sections perpendicular to this lumen. Agreements and reliability of measurement methods were assessed by intra-class correlation coefficient and Bland - Altman analysis. Discordances between measurements of the methods and the original reported measurement, as well as outside hospitals were compared. RESULTS: The average age of the cohort was 75 years and aortic diameters ranged from 3.8 to 9.6 cm. For orthogonal readings, there were agreements within 3 mm between 86% and 92% of the time, while centerline - reading agreement was between 88% and 94%, which was not statistically significant. The intra-class correlation coefficient was high between method type and between readers. Within methods, agreement was between 0.96 and 0.97, while within - reader agreement measures was between 0.96 and 0.98. In comparison to the original and the outside hospital reports, 10% ≥ of the original and 20% ≥ of the outside hospital reported measurements were discordant between the readers. CONCLUSION: Maximal AAA measurements can have substantial variability leading to clinical significance and change in patient management and outcomes. Based on the results, orthogonal and centerline measurement methods have equally high agreements and concordance within 3 mm and low variations at a high volume center. However, when compared to the official read reports, there is high discordance rates that can significantly alter patient outcomes. A standardized method of measurement maximum diameter can reduce variations and discordances among different methods.

A bio-inspired computing model for ovarian carcinoma classification and oncogene detection.

MOTIVATION: Ovarian cancer is the fifth leading cause of cancer deaths in women in the western world for 2013. In ovarian cancer, benign tumors turn malignant, but the point of transition is difficult to predict and diagnose. The 5-year survival rate of all types of ovarian cancer is 44%, but this can be improved to 92% if the cancer is found and treated before it spreads beyond the ovary. However, only 15% of all ovarian cancers are found at this early stage. Therefore, the ability to automatically identify and diagnose ovarian cancer precisely and efficiently as the tissue changes from benign to invasive is important for clinical treatment and for increasing the cure rate. This study proposes a new ovarian carcinoma classification model using two algorithms: a novel discretization of food sources for an artificial bee colony (DfABC), and a support vector machine (SVM). For the first time in the literature, oncogene detection using this method is also investigated. RESULTS: A novel bio-inspired computing model and hybrid algorithms combining DfABC and SVM was applied to ovarian carcinoma and oncogene classification. This study used the human ovarian cDNA expression database to collect 41 patient samples and 9600 genes in each pathological stage. Feature selection methods were used to detect and extract 15 notable oncogenes. We then used the DfABC-SVM model to examine these 15 oncogenes, dividing them into eight different classifications according to their gene expressions of various pathological stages. The average accuracyof the eight classification experiments was 94.76%. This research also found some oncogenes that had not been discovered or indicated in previous scientific studies. The main contribution of this research is the proof that these newly discovered oncogenes are highly related to ovarian or other cancers. AVAILABILITY AND IMPLEMENTATION: http://mht.mis.nchu.edu.tw/moodle/course/view.php?id=7.

Evaluation of Polymeric Nanomedicines Targeted to PSMA: Effect of Ligand on Targeting Efficiency.

Targeted nanomedicines offer a strategy for greatly enhancing accumulation of a therapeutic within a specific tissue in animals. In this study, we report on the comparative targeting efficiency toward prostate-specific membrane antigen (PSMA) of a number of different ligands that are covalently attached by the same chemistry to a polymeric nanocarrier. The targeting ligands included a small molecule (glutamate urea), a peptide ligand, and a monoclonal antibody (J591). A hyperbranched polymer (HBP) was utilized as the nanocarrier and contained a fluorophore for tracking/analysis, whereas the pendant functional chain-ends provided a handle for ligand conjugation. Targeting efficiency of each ligand was assessed in vitro using flow cytometry and confocal microscopy to compare degree of binding and internalization of the HBPs by human prostate cancer (PCa) cell lines with different PSMA expression status (PC3-PIP (PSMA+) and PC3-FLU (PSMA-). The peptide ligand was further investigated in vivo, in which BALB/c nude mice bearing subcutaneous PC3-PIP and PC3-FLU PCa tumors were injected intravenously with the HBP-peptide conjugate and assessed by fluorescence imaging. Enhanced accumulation in the tumor tissue of PC3-PIP compared to PC3-FLU highlighted the applicability of this system as a future imaging and therapeutic delivery vehicle.

Hybrid PET/MR imaging: physics and technical considerations.

In just over a decade, hybrid imaging with FDG PET/CT has become a standard bearer in the management of cancer patients. An exquisitely sensitive whole-body imaging modality, it combines the ability to detect subtle biologic changes with FDG PET and the anatomic information offered by CT scans. With advances in MR technology and advent of novel targeted PET radiotracers, hybrid PET/MRI is an evolutionary technique that is poised to revolutionize hybrid imaging. It offers unparalleled spatial resolution and functional multi-parametric data combined with biologic information in the non-invasive detection and characterization of diseases, without the deleterious effects of ionizing radiation. This article reviews the basic principles of FDG PET and MR imaging, discusses the salient technical developments of hybrid PET/MR systems, and provides an introduction to FDG PET/MR image acquisition.

Improving the biodistribution of PSMA-targeting tracers with a highly negatively charged linker.

BACKGROUND: Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer and in tumor vasculature. Small molecule based inhibitors of PSMA have promised to provide sensitive detection of primary and metastatic prostate tumors. Although significant progress has been made, many of the radiolabeled imaging agents exhibit non-specific background binding. Prevailing tracer designs focus on high affinity urea-based inhibitors with strategically placed hydrophobic patches that interact favorably with the substrate tunnel of PSMA. We hypothesized that a novel PSMA inhibitor design incorporating highly negatively charged linkers may minimize non-specific binding and decrease overall background. METHODS: Through iterative redesign, we generated a series of PSMA inhibitors with highly negatively charged linkers that connect to urea inhibitors and bulky radionuclide chelates. We then performed in vivo imaging and biodistribution studies with the radiolabeled tracers. RESULTS: The tracers derived from our iterative redesign have affinities for PSMA comparable to the "parent" urea ligand Cys-C(O)-Glu. Using a fluorine-18 labeled PSMA targeting tracer, we found that these highly negatively charged molecules exhibit rapid renal excretion with minimal non-specific binding. The biodistribution data at 2 hr showed 4.6%ID/g PC3-PIP tumor uptake with spleen, liver, bone, and blood background levels of 0.1%, 0.17%, 0.1%, and 0.04%, respectively. CONCLUSION: Placement of multiple negative charges in the linker region of PSMA tracers significantly reduced the non-specific background binding without significant reduction of binding affinity. This increased tumor/background contrast in positron emission tomography promises to provide more sensitive tumor detection while decreasing the overall radiation exposure to patients.

Ictal single photon emission computed tomography in epileptic auras.

OBJECTIVES: Little is known about whether ictal single photon emission computed tomography (SPECT) during an isolated aura can localize the epileptogenic zone (EZ). This study seeks to evaluate the yield of ictal SPECT injection in isolated epileptic auras. METHODS: We identified 20 patients with focal epilepsy studied during 26 isolated auras by ictal interictal subtraction SPECT coregistered to magnetic resonance imaging (SISCOM). Studies were rated by two readers who blindly scored the images for presence or absence of an area of dominant hyperperfusion and the lateralization and localization of ictal hyperperfusion; kappa statistics were calculated. Results are correlated with the localization or lateralization of the EZ, time of injection, and electroencephalography (EEG) findings during aura. RESULTS: Fourteen (53%) of 26 injections in 13 patients were rated by both readers as having an area of dominant hyperperfusion with poor interobserver agreement (k = 0.128). Nine of 26 injections in eight patients were correctly lateralized to the side of the EZ (κ = 0.46), but only one of 21 injections in one patient was correctly localized (κ = 0.146). No difference was found when comparing temporal and extratemporal cases. Studies obtained in auras with ictal EEG change were no more likely to be correctly localized than in ones without (p = 0.19). The timing of injection was not a predictor of success. SIGNIFICANCE: Ictal SPECT injection during an isolated aura has a low yield of correct localization of the EZ and cannot be relied on alone during presurgical evaluation. A repeat injection during a seizure with clinical signs and ictal EEG accompaniment is recommended.

A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11.

BACKGROUND: The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting prostate specific membrane antigen (PSMA). Prior work on a similar tracer with the same negatively charged linker demonstrated low normal organ/soft tissue background uptake compared to [68Ga]Ga-PSMA-11. The purpose of this study was to investigate if [68Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11. RESULTS: JB-1498 demonstrated high affinity for PSMA binding and tumor uptake in a murine tumor model. In an initial biodistribution study with low molar activity, [68Ga]Ga-JB-1498 demonstrated salivary gland uptake of 0.13 ± 0.01%ID/g. In a second biodistribution study in non-tumor-bearing mice with high molar activity, [68Ga]Ga-JB1498 demonstrated salivary gland uptake of 0.39 ± 0.24% ID/g and kidney activity of 10.12 ± 1.73% ID/g at one hour post IV injection. This salivary gland uptake is significantly less than the published uptake of [68Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [68Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [68Ga]Ga-PSMA-11 activity in these two organs during the first hour. CONCLUSION: Biodistribution and micro-PET imaging of [68Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [68Ga]Ga-PSMA-11. Our findings suggest that constructing a PSMA-targeting molecule with a highly negatively charged linker is a promising strategy to reduce salivary gland uptake of GCP-II/PSMA ligands in theranostic applications.

Multi-Modality Imaging in Vasculitis.

Systemic vasculitides are a rare and complex group of diseases that can affect multiple organ systems. Clinically, presentation may be vague and non-specific and as such, diagnosis and subsequent management are challenging. These entities are typically classified by the size of vessel involved, including large-vessel vasculitis (giant cell arteritis, Takayasu's arteritis, and clinically isolated aortitis), medium-vessel vasculitis (including polyarteritis nodosa and Kawasaki disease), and small-vessel vasculitis (granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis). There are also other systemic vasculitides that do not fit in to these categories, such as Behcet's disease, Cogan syndrome, and IgG4-related disease. Advances in medical imaging modalities have revolutionized the approach to diagnosis of these diseases. Specifically, color Doppler ultrasound, computed tomography and angiography, magnetic resonance imaging, positron emission tomography, or invasive catheterization as indicated have become fundamental in the work up of any patient with suspected systemic or localized vasculitis. This review presents the key diagnostic imaging modalities and their clinical utility in the evaluation of systemic vasculitis.

Novel Depiction of Collateral Flow in Chronic Thromboembolic Pulmonary Hypertension Using 4D Dynamic 82 Rb PET/CT.

ABSTRACT: CT pulmonary angiogram and ventilation-perfusion scintigraphy are the 2 primary imaging modalities for evaluating patients with CTEPH (chronic thromboembolic pulmonary hypertension). PET/CT and MRI currently have a limited role in the evaluation of acute or chronic pulmonary embolism. We present incidentally captured dynamic pulmonary perfusion images in a patient with history of CTEPH who underwent 82 Rb myocardial perfusion PET/CT for evaluation of chest pain. Analysis of the PET data revealed delayed perfusion of the affected lobes suggesting collateralization, highlighting a potentially new imaging paradigm for assessment of pulmonary perfusion.

Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium. Each family's CNV data was analyzed using the seqr platform and candidate CNVs classified using the 2020 ACMG/ClinGen CNV interpretation standards. We developed additional evidence criteria to address situations not covered by the current standards. The addition of CNV calling to exome analysis identified causal CNVs for 173 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb with estimates that 44% would not have been detected by standard chromosomal microarrays. The causal CNVs consisted of 141 deletions, 15 duplications, 4 suspected complex structural variants (SVs), 3 insertions and 10 complex SVs, the latter two groups being identified by orthogonal validation methods. We interpreted 153 CNVs as likely pathogenic/pathogenic and 20 CNVs as high interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

The financial burden of mandibular trauma.

PURPOSE: Patients with mandibular trauma in the greater Seattle region are frequently transferred to Harborview Medical Center (HMC) despite trained providers in the surrounding communities. HMC receives poor reimbursement for these services, creating a disproportionate financial burden on the hospital. In this study we aim to identify the variables associated with increased cost of care, measure the relative financial impact of these variables, and quantify the revenue loss incurred from the treatment of isolated mandibular fractures. MATERIALS AND METHODS: A retrospective chart review was conducted of patients treated at HMC for isolated mandibular fractures from July 1999 through June 2010, using International Classification of Diseases, Ninth Revision and Current Procedural Terminology coding. Data collected included demographics, injury, hospital course, treatment, outcomes, and billing. RESULTS: The study included 1,554 patients. Total billing was $22.1 million. Of this, $6.9 million was recovered. We found that there are multiple variables associated with the increased cost of treating mandibular fractures; 4 variables--length of hospital stay, treatment modality, service providing treatment, and method of arrival--accounted for 49.1% of the total variance in the amount billed. In addition, we found that the unsponsored portion of our patient population grew from 6.7% to 51.4% during the study period. CONCLUSIONS: Our results led to specific cost-efficiency recommendations: 1) perform closed reduction whenever possible; 2) encourage performing procedures with patients under local anesthesia (closed reductions and arch bar removals); 3) provide improved and shared training among the services treating craniofacial trauma; 4) encourage arrival by privately owned vehicle; 5) provide outpatient treatment, when applicable; 6) offer provider incentives to take trauma call; and 7) offer hospital incentives to treat patients and not transfer them.

Imaging of Tumor-Associated Vascular Prostate-Specific Membrane Antigen in Woodchuck Model of Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Radiolabeled short peptide ligands targeting prostate-specific membrane antigen (PSMA) were developed initially for imaging and treatment of prostate cancers. While many nonprostate solid tumors including hepatocellular carcinoma (HCC) express little PSMA, their neovasculature expresses a high level of PSMA, which is avid for Gallium-68-labeled PSMA-targeting radio-ligand (68Ga-PSMA-11) for positron emission tomography (PET). However, the lack of a spontaneous animal model of tumor-associated vascular PSMA overexpression has hindered the development and assessment of PSMA-targeting radioligands for imaging and therapy of the nonprostatic cancers. We identified detectable indigenous PSMA expression on tumor neovascular endothelia in a naturally occurring woodchuck model of HCC. METHODS: Molecular docking was performed with 3 bait PSMA ligands and compared between human and woodchuck PSMA. Initially, PET images were acquired dynamically after intravenously injecting 37 MBq (1.0 mCi) of 68Ga-PSMA-11 into woodchuck models of HCC. Subsequently, 10-minute static PET scans were conducted for other animals 1-hour after injection due to HCC and liver background uptake stabilization at 30-45 minutes after injection. Liver tissue samples were harvested after imaging, fresh-frozen for quantitative reverse transcription polymerase chain reaction and western blot for validation, or fixed for histology for correlation. RESULTS: Our preclinical studies confirmed the initial clinical findings of 68Ga-PSMA-11 uptake in HCC. The agents (ligands and antibodies) developed against human PSMA were found to be reactive against the woodchuck PSMA. CONCLUSION: This animal model offers a unique opportunity for investigating the biogenesis of tumor-associated vascular PSMA, its functional role(s), and potentials for future treatment strategies targeting tumor vascular PSMA using already developed PSMA-targeting agents.

Assessment of ventilation-perfusion scans in patients with chronic thromboembolic pulmonary hypertension before and after surgery and correlation with clinical parameters.

PURPOSE: We did a comparative analysis of matched and mismatched defects in pre- and post-operative V/Q scans in CTEPH patients. We correlated the number of these defects with pre-operative clinical and hemodynamic parameters. METHODS: This was a retrospective study on 27 patients with CTEPH who underwent surgery. Pre- and post-operative V/Q scans were graded for each lung segment as normal, matched or mismatched defect. Additional pre- and post-operative clinical and hemodynamic parameters that were collected include New York Heart Association functional class, six-minute walk distance in feet, N-terminal pro b-type natriuretic peptide, forced expiratory volume in one second/forced vital capacity, diffusing capacity of the lung for carbon monoxide, pulmonary arterial pressure (systolic, diastolic and mean), right atrial pressure, cardiac output and cardiac index. Pulmonary vascular resistance was then calculated. RESULTS: On a segmental basis, 176 mismatched defects were noted in 27 patients, of which 111 improved post-surgery (63%). 22 of the 34 matched defects improved following surgery (64%). 31 new mismatched defects were observed. The number of pre-operative matched defects per patient ranged from 0 to 6. No statistically significant associations were observed between the number of pre-operative matched defects and pre-operative clinical parameters. No statistically significant associations were observed between the number of improved matched defects and the change in clinical parameters (pre- to post-surgery). CONCLUSION: Both matched and mismatched defects on preoperative V/Q scans can show normalization post-surgery. The extent of matched defects on a preoperative V/Q scan does not correlate significantly with other clinical and hemodynamic parameters.

Identification of Myocardial Telocytes and Bone Marrow Mesenchymal Stem Cells in Mice.

OBJECTIVES: The aim of this study was to compare the morphology, immune phenotype, and cytokine profiles between myocardial telocytes (TCs) and bone marrow mesenchymal stem cells (MSCs), and explore the difference between those two types of interstitial cells. METHODS: TCs and MSCs were cultured in vitro and cell morphology was observed with a light microscope. The expression levels of CD34, c-kit, and vimentin were detected by immunofluorescence, RT-qPCR, and Western blotting in both TCs and MSCs. The related supernatant was collected and total of 49 cytokine profiles were detected by RayBio Mice Cytokine Antibody Array. Significantly different cytokines were further confirmed by ELISA. RESULTS: TCs have small cellular body and very long prolongations and they were CD34+/c-kit+/vimentin+, whereas MSCs have no telopodes and they were CD34-/c-kit- /vimentin+. Cytokine profile analysis and ELISA showed that 19 of 49 cytokines were increased dramatically in the supernatant of TCs compared with those of MSCs. Moreover, 9 of 19 cytokines were increased 2-fold at least in the supernatant of TCs compared with those of MSCs. Of 49 cytokines, 30 exhibited no significant changes in the supernatant of TCs compared with those of MSCs. CONCLUSIONS: Using various technologies, we identified that myocardial TCs and MSCs are significantly different in terms of cell structure and cytokine profiles.

A Perspective on the Evolving Story of PSMA Biology, PSMA-Based Imaging, and Endoradiotherapeutic Strategies.

In this review, we cover the evolution of knowledge on the biology of prostate-specific membrane antigen (PSMA) and its translation to therapy. The usual key to discovery is a realistic model for experimentation and for testing a hypothesis. A realistic model is especially needed in the case of the human prostate, which differs significantly from the prostate of species often used as research models. We will emphasize the genetic characterization of PSMA, the nature of the PSMA protein, and its role as a carboxypeptidase, with differing important substrates and products in different tissues. We give special prominence to the importance of PSMA as a target for imaging and therapy in prostate cancer and its underdeveloped role for imaging and targeting the neovasculature of tumors other than prostate cancer. Lastly, we bring attention to its importance in other nonprostatic tissues.